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The Faces of Successful Colorectal Cancer Immunotherapies: Vol. 1

I wanted to expand the normal scope of my personal blog in today’s post. Not just for the sake of expansion but importantly because I believe strongly in today’s topic! After a bit of introductory science, I will be profiling two fellow CRC patients currently in immunotherapy clinical trials – to illustrate the preliminary signs of immunotherapy success of checkpoint PD-1 pathway inhibition in a significant percentage of patients with MSI-high CRC. These may be the first Stage IV cancer clinical trial participants you have ever met – in my current life I am surrounded by heroes like them every day. I think this post will have a positive impact both on readers who have been touched by CRC as well as on my fellow scientist readers. If you agree after reading it, I ask that you share it with every CRC patient you know.

My The Currently Incurable Scientist monthly column that published yesterday, “Releasing the PD-1 Brakes in MSI-high CRC Patients”, was all about explaining in a brief, easily understood way the importance of CRC patients knowing and getting tested for their “Microsatellite (MSI) status”. I want to explain here how incredibly important I believe knowing your MSI-status is for all CRC patients. The test for it can be ordered by a doctor using archived tissue samples. This personal blog post is a deeper dive into the topic, consider it the Director’s Cut…

The PD-1 pathway exists for good reason: to protect the body from autoimmune disease by “putting brakes on the immune system”. In cancer, tumors can sometimes hijack this system to escape immune attack. PD-(L)1 inhibitors therefore “release the immune system brakes” allowing the immune system to successfully attack tumors in some patients!

To briefly restate the key message: based upon preliminary clinical trial data, MSI-status appears likely to bea very good “biomarker” to predict which CRC patients will most likely respond to the current hottest immunotherapies (PD-(L)1 inhibitors), at least when these drugs are used alone as monotherapies.

The preliminary clinical trial data using the PD-1 inhibitor Keytruda (pembrolizumab) was presented at ASCO-2015 and published in the New England Journal of Medicine. In the small trial, 9 out of 10 evaluable “MSI-high” CRC patients showed disease control (4 with at least 30% tumor shrinkage & 5 with stable disease of at least 3 months). Although the data shown is in very small patient numbers, it is simply too striking to ignore unless proven otherwise with subsequent clinical data. This is especially true in the Stage IV world where lives are literally at stake and to be blunt, many patients’ “life timelines” do not have the luxury of waiting for full data confirmation before strategizing treatment and clinical trial choices with their MD. That is not a medical opinion (I’m not a MD!) but it is certainly my personal opinion as a Stage IV patient!

Microsatellite Instable-high (MSI-high; “Mismatch-repair deficient”) CRC patients appear most likely to respond to monotherapy PD-1 pathway inhibition; Microsatellite Stable (MSS; “Mismatch-repair proficient”) CRC patients appear much less likely to respond. This is of course based upon data currently in hand from a very small trial.

Scientifically this clinical observation would make a lot of sense since MSI-high tumors both usually have much higher numbers of mutations which can catch the immune system’s attention as well as often large numbers of immune cells already present near the tumor. That situation is a match made in Heaven in the world of immuno-oncology!

Larger trials using PD-(L)1 inhibitors against MSI-high CRC are in progress and their results are eagerly being anticipated. If the results of the small preliminary trial are confirmed, this would be the biggest scientific leap in the treatment for MSI-high CRC patients in decades!

Multiple PD-(L)1 inhibitor trials are currently in progress and open to MSI-high CRC patients – both in the case of monotherapies as well as various experimental drug combination cocktails. If you have MSI-high CRC, the Cancer Research Institute’s Immunotherapy Trial Finder is a great information resource to find these trials to discuss with you doctor.

Aside from reiterating my strong personal beliefs on the importance of knowing your MSI-status, I wanted to use today’s post for something very special. I wanted to profile two MSI-high patients who are currently in PD-(L)1 inhibitor immunotherapy clinical trials to show you the faces & stories of the people behind these groundbreaking studies. I hope hearing their stories is inspirational to my fellow cancer patients. I also hope hearing and seeing them is inspirational to my fellow scientists who are currently working on next generation cancer immunotherapies. As a person with “a foot in both camps” it has always been a goal of this blog to bring these two components of the cancer world together to inspire each other!

A Very Important Disclaimer

Before I dive into the profiles, I have to mention that PD-1 pathway inhibition does NOT have a 100% response rate even for MSI-high CRC and significant toxicity is possible. Thus, although Leta and Stephen are doing great so far on the therapies in terms of both efficacy and safety – there is no guarantee that their experience will be similarly experienced by another patient. That is simply the nature of medicine (especially experimental medicines!) – all patients are different in terms of efficacy & side effect/toxicity response. Keeping that in mind, here are their inspirational personal stories…

Leta Withers – CRC Immunotherapy Pioneer

Leta was a happy wife & mother of 3 boys, aged 9, 13 & 16 when she first experienced the symptoms of colon cancer at only 46 years old. As is often the case for patients under 50, her symptoms were mistakenly attributed to other causes until she insisted on a colonoscopy. She had been warned that due to her age, insurance probably wouldn’t cover it – but Leta insisted since she had just had two friends under 45 diagnosed with CRC. Leta doesn’t back down easily when she sees an opportunity she knows she has to take.

They found an egg sized tumor in her right colon. 11 of 23 lymph nodes were positive for cancer so she was classified Stage 3C. After 4 months of the grueling cytotoxic XELOX/CAPOX chemotherapy cocktail, her scans were clean. Unfortunately only 3 months later, tumors were found in her lung, chest lymph node, ovary, and peritoneum. She was now declared inoperable Stage IV – or as I prefer to say, she was at that point declared currently incurable…

She was terrified in private. She knew what the prognosis for inoperable Stage IV CRC was. She flew to MD Anderson for a second opinion. It was there that she first heard about the “MSI-high” biomarker and the good responses they were seeing there in PD-(L)1 inhibitor trials. Leta is in the group of 10-15% of sporadic CRC patients who are MSI-high.

Looking at her current quality of life and having performed a lot of self-education on checkpoint inhibitor immunotherapies & MSI-high CRC – Leta decided to do the clinical trial instead. Slots were very limited so she had to call many times over multiple months. She finally was offered a slot – but she needed to decide without delay whether to take the “Clinical Trial plunge” or continue standard chemo. She decided to go for the trial.

Leta signed the required paperwork and started the trial within days. In her own words: “It was nothing like the chemo I had endured. I left the chemo chair feeling terrific. No nausea, no pain, no fatigue! I was hungry and felt like myself! After the first treatment, I had wine and cheese and went shopping! Just a tad different than previous chemo.” The only side effect she has endured is elevated liver enzymes. She has had 3 scans so far – they have showed shrinkage or stability in all her lesions.

To close with her own words: “I credit this drug hugely with both my favorable scans and mostly the amazing quality of life it has given me back. I feel like my old self again. I don’t feel sick, and I have no down days anymore. I feel like I drew the lucky card to be MSI-high and have the chance to be on this trial!”

Pictured below are 1.) Leta looking over trial information papers and 2.) her feeling great while on trial. A video interview with her can be watched here.

Stephen Estrada – CRC Immunotherapy Pioneer

Stephen was diagnosed with Stage IV CRC at the very young age of 28. He was fresh out of school and excited to start his career. Life was fantastic until GI-symptoms became too great to ignore. Because of his young age, his symptoms were not taken seriously even during two trips to the ER. Thankfully his primary care physician took his concerns seriously and a tumor was found in his colon – but at the time of diagnosis it had already metastasized to his mesentery.

He underwent surgery followed by 6 months of the difficult FOLFOX cytotoxic chemotherapy cocktail. The chemo was very rough – his weight bottomed out at 110 lbs and he looked obviously very sick to everyone that saw him. A radiosurgery was attempted to remove a remaining tumor but it failed. Before his 30th birthday, Stephen was declared inoperable Stage IV. At that point, declared currently incurable.

He transferred his care to the University of Colorado Cancer Center. As is often the case in patients diagnosed that young, genetic testing revealed that Stephen has Lynch Syndrome – and he is also MSI-high. His new oncologist was familiar with good preliminary clinical trial results being seen with PD-1 pathway checkpoint inhibitors in MSI-high CRC patients. Based upon his new doctor’s advice, Stephen started a Phase 1 clinical trial of the PD-L1 inhibitor MPDL3280a (atezolizumab) + Avastin (bevacizumab).

In Stephen’s own words: “As I received my first infusion, I was overcome with severe back pain that lasted about two days…but after it left up, I realized that all my tumor induced pain seemed to have already faded away. The second infusion landed me in the hospital for 5 days when I started running a fever of 104. The strange thing is…I never felt very sick…just hot. A whole barrage of tests were ordered to see if there was an infection attacking me. Nothing ever came up and the fever was attributed to the MPDL3280a revving up my immune system and recognizing the cancer.”

Stephen has had 3 scans while on trial – after an initial shrinkage of his tumors, the 2 follow-up scans show stable disease.To close with his own words: “Besides my disease being held in check, the best thing is…I feel wonderful. I have gained about 40 lbs, I am able to be in the gym about 5 days a week, and I am currently in the process of returning back to work. Without this drug, I would be thin, ill, and potentially not alive.”

Pictured below are 1.) Stephen during chemo contrasted with him currently on PD-L1 immunotherapy and 2.) him exuberantly living life with a group of friends at a recent CRC patient advocacy event.

I have to thank both Leta and Stephen for allowing me to share their stories! I believe clinical trial participants are incredibly brave heroes.Incredibly brave because they are subjecting their bodies to medicines without fully known safety or efficacy. Heroes because the data generated using their bodies (whether positive or negative) is used to help guide the treatment of all other future & current CRC patients!

I think both Leta’s and Stephen’s stories illustrate both the hope and potential of the paradigm shift in cancer treatment towards immunotherapies currently sweeping through oncology. As a scientist – and as a Stage IV patient – it is truly amazing to see. Unfortunately there remains a lot of work left to do. Even in the cancer types with the highest response rates (e.g. melanoma) many patients do not respond. Even though some patients show very long term responses, most do not. There are also cancer types (e.g. MSS CRC – the kind of CRC I have) which are not responding well yet to immunotherapy drugs, based upon clinical data known as of today. For all these reasons – research is being done at a furious rate to “increase response rates” (i.e. increase the number of patients who respond) as well as to “increase duration of action” (i.e. increase the length of responses aiming for the ultimate goal = “forever” i.e. cures!).

Science is always full of surprises – both negative and positive – that is the nature of trying things for the first time. All I know for certain is that both response rates and duration of actions will increase – the only unknowns are the specific “whens” and “hows”.

I once again urge all CRC patients to discuss MSI testing with their MD. What we are seeing right now, illustrated by Leta and Stephen, is just the tip of the iceberg. I honestly believe the future of cancer immunotherapy will be breathtaking to behold. Fasten your seat belts…

July 2016 update:

Unfortunately Leta passed away in July of 2016 after describing her time on immunotherapies as the best time period of her Stage IV life. She was a fierce advocate for educating and empowering CRC patients for immunotherapy clinical trials – she reached tens of thousands of fellow patients worldwide through her advocacy and her legacy will live on! Her life & death illustrate both the preliminary promise in CRC immunotherapies as well as the need for additional clinical trial combination therapies even for the MSI-high CRC patient community.

Great article! Very interesting and exciting!! We also are hopeful that there will be a breakthrough in immunologic treatments for CRC MSS patients! My husband is currently in the TAS-102 clinical trial until this new FDA approved chemo drug becomes commercially available. So far he’s tolerating it well and his QOL is good! We really wanted to get into a immunology trial but he didn’t qualify for any of them.

Thank you Sarah!
I have been monitoring the various PD-(L)1 combo trials including the IDO/pembro one. I’m particularly interested in that one since my own tumor over-expresses IDO1 – but unless I missed it (in the data deluge always possible), I don’t think they have released CRC clinical data yet? Please post a link if you know of any released CRC clinical data!

Hi, I don’t have any results at this time, need to research further myself. I have gastric cancer and need to find my next treatment and I am considering all the options too. My preferred route is immunotherapy.
There are so few options that I need to extrapolate from other cancer types/trials to assess which will be a good fit for me.
Thanks for taking the time to respond

Thank you for this informative and inspirational post. I am one of the Lynch disease patients in Dr. Dung Le’s clinical trial at Johns Hopkins Hospital. This coming January will be two years since I began the PD-1 inhibitor medicine, and I am blessed to be among the group that has had phenomenal response to the treatment. My scans show either stable or shrinking disease and no new growth. I feel wonderful, much as Leta describes above. I pray for this treatment to become more widely available and effective for other CRC patients. It has been an exciting and humbling experience. We patients need to advocate for ourselves and continue to urge our doctors to become educated about genetic CRC. Thanks.

Thank you for taking the time to write this comment/tell your story Kate, hearing from you will be further inspiration to my blog’s readership! I am very glad that PD-1 inhibition is controlling your CRC and I wish you all the best. Please continue your advocacy! -Tom

Thank you for sharing. My husband could have been in this story, as he has a similar story. He was diagnosed at 46 with Stage 4 CRC with liver mets. The only segment of his liver that was not involved was lobe III. This means 7/8 of his liver was diseased, and he was not even a candidate for a resection. We were told that it was everywhere, and he would not have a liver left if he had surgery. He went through 16 rounds of chemo before starting on Opdivo (Nivolumab). His first scans showed an overall shrinkage of 12%, and then 55%. August 30, 2014 the radiology report read NED. He will have a biopsy tomorrow while in surgey for another issue, and hopefully we will get a NED report from the doctor. Yes, the radiology report states it, but there is something about the doctor agreeing with the findings. They did not give him much of a change 2.5 years ago, but we kept the faith, never gave up, and have seen the results. If you want to know more, please feel free to contact me on facebook.

Hi Laura,
Thank you for sharing your husband’s story! His is yet another similar story I have heard now numerous times from the MSI-high CRC community. I am thrilled to hear all of these stories and thrilled at his response!
Please give him my best & take care,
Tom

Hi Bridget – the MSI/MSS test is completely separate from the KRAS test. What this means is that you should talk to your MD and ask if your MSI-status is known/already in your files (it may be there without you knowing). If it has not been tested, you should ask your MD to order the test. If it is already known & you are MSI-high, you should discuss with your MD the PD-1 immunotherapy trials in progress. There are files hyperlinked in the webpage link that I pasted below to bring to your MD to facilitate the discussion – they are the recommendations from the AGA that all CRC patients be tested for MSI-status as well as the New England Journal of Medicine preliminary clinical trial results. Best of luck to you- http://fightcolorectalcancer.org/research-treatment/currently-incurable-scientist/releasing-the-pd-1-brakes-in-msi-high-crc-patients/

My husband is part of the PDL-1 trial at MD Anderson. He is an MSI high colorectal patient stage IV and has had significant tumor necrosis and has not progressed in a year he has been on trial. Several tumors have disappeared There is hope and the future holds great opportunities in treatment for colorectal cancer – This I believe and am witnessing it daily. Keep strong and raise awareness…we WILL get there!!

Hi Sandra – Thank you for sharing your husband’s high and durable response! I love it when fellow survivors/caregivers post their immunotherapy stories of success as comments to this story. A purpose of the way I wrote this blog post was to humanize the scientific breakthrough – and these comments further that cause! Wishing your husband & you the very best, -Tom

I have a question. My husband has not MSI high tumor. But we have just made test Metavectum from Circulating Tumor Cells and there we see clearly that there is high gene profile of PD1 PDL1 genes expression. Does it mean that it is worth trying Keytruda or Opdivo ? Or just the fact that it is not MSI high tumor means it will not respond to it? I would like to attach this test, so you could see it to maybe beter understand what I mean but I do not know how to do it.
Thank you for your help !

That is a fantastic question Anna. I don’t know the level of oncologist you are currently seeing but as a patient, if I were presented by data such as that I would bring it for second opinion MD discussion at a NCI-designated Cancer Center – ideally one with a very heavy immunotherapy focus such as Johns Hopkins & MSKCC – but for sure a NCI-designated center, great ones exist on both coasts as well as e.g. MD Anderson and U Colorado in the interior. The gene expression profile is very interesting and after MD assessment, the possibility of off-label compassionate use of Keytruda exists. After MD follow-up, please post a follow-up comment the results! Best of luck to your husband! -Tom

Unfortunately we live in Belgium not in USA, pity !
Our oncologue here is quite sceptical about this test. I do not know where I should ask this question to get a good answer. I tried to find a contact with Keytruda producer, but for the moment I do not find a way. There was a contact to dr who makes clinical trials with Keytruda in Belgium, but telephone doesn’t answer.
Have you any idea, how to get an answer from Keytruda or Opdivo producer if this gene expression is just worth nothing.
I am still searching, and I will search, but time is so important !

You will need a MD assessment, in the United States we have higher level “NCI-designated” cancer centers that are specially certified for oncology where many patients get second opinions especially for unique cases or questions – often they are Universities in addition to large cancer centers like Memorial Sloan Kettering in New York City or MD Anderson in Texas. I don’t know, does a similar system for second opinions exist in Belgium? In terms of Keytruda producer contact, here is a hyperlink for a contact route for their patient assistance program. They can answer some basic questions as well as help if you have a MD assessment that determines asking for their help would be a good addition to your treatment plan. https://www.merckaccessprogram-keytruda.com/hcc/

I’ve just had my first dose or pembro today. Don’t know my MSI status. My onco says to try it out and look for a clinical response in 3 months. Have been living with CRC stage 4 for 7 1/2 years. Been on every possible chemo and surgical procedure. No reimbursement in my country so it’s a pretty expensive mode of treatment. One cycle cost about USD 8000. ouch…….Hope it works for me…..got to work harder from now on…

Thank you for providing this information. My daughter was diagnosed with advanced bowel cancer (inoperable liver mets) in May 2015 at age 28, She immediately commenced chemotherapy, In July 2015 her biopsy revealed MSHI MMRD but despite the ASCO report her oncologist felt obliged to continue with conventional treatment including selective radiation to her liver mets and another round of chemo. She responded well so he gave her a short break from treatment. Within six weeks the liver mets had increased in number and size and she had early stages of ascities. By this time it was November & the oncologist said if we could afford to pay my daughter should start KEYTRUDA immediately. The past six months have been amazing my daughter has been able to attend work and enjoy a ‘normal’ life and this week a colonoscopy revealed the once lemon size tumour is a now (removed) 9mm polyp. The tumours in her liver have also greatly reduced in size. We live in Australia where patients with advanced Melanoma receive Keytruda for $40 a treatment. Unfortunately for patients with other conditions it is seen as experimental and therefore not funded. Funding this breakthrough treatment is a big hurdle hopefully the price will fall as it can be used for more types of cancers.

Hi Tom, found out about your blog through Colon Talk. I was diagnosed Stage 3b in June of this year at 42. Had the surgery and have begun on Folfox. My tumour is MSI high and I found this post very encouraging. I was wondering if trials are only for Stage 4 patients or do Stage 3 patients qualify? I am also Canadian so I don’t know if there is any overlap between our countries for these.
Thanks for any answers you might have. 🙂
Beth

Hello,
I am 43 yr old father of two and was diagnosed with stage IV CRC last year. I am MSI High.
After 9 rounds of Capox and 4 of Avastin , I have started with Nivulumab last month.
Getting so much hope after reading blogs here. Thanks.
Well being has improved and some increase in weight . Try to do yoga everyday. Tests after 6 rounds.
Fingers crossed.
Best wishes for all.